2. Academic Validation
  3. Retinoic Acid Reprograms Mast Cells Toward a Proinflammatory State to Enhance Antitumor Immunity

Retinoic Acid Reprograms Mast Cells Toward a Proinflammatory State to Enhance Antitumor Immunity

  • Adv Sci (Weinh). 2025 Nov 27:e09340. doi: 10.1002/advs.202509340.
Lizao Zhang 1 2,  Siqi Ren 1 2,  Yuhui Li 2 3,  Rongxi Chen 1 2,  Ling Qiu 1 2,  Yongmei Tan 1 2,  Suling Chen 1 2,  Huiqian Wu 3,  Lianxi Mai 1 2,  Xiao Tan 1 2,  Xin Liu 4 5,  Peisheng Liang 6,  Shijia Kuang 1 2,  Liansheng Wang 1 2,  Jingkang Liu 1 2,  Jintao Li 1 2,  Yanyan Li 1 2,  Qiuping Xu 2 7,  Yongzhi Su 8,  Yuehai Luo 8,  Binyan Wu 8,  Zijing Huang 9,  Haotian Cao 1 2,  Qunxing Li 1 2,  Jinsong Li 1 2,  Tianjun Lan 1 2
Affiliations

Affiliations

  • 1 Department of Oral and Maxillofacial Surgery, Sun Yat-sen Memorial Hospital of Sun Yat-sen University, Guangzhou, 510120, China.
  • 2 Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Medical Research Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, 510120, China.
  • 3 Department of Pathology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, 510120, China.
  • 4 Department of Stomatology, Affiliated Hospital of Hangzhou Normal University, Hangzhou, 310015, China.
  • 5 Department of Stomatology, Shunde Hospital, Southern Medical University (The First People's Hospital of Shunde), Foshan, 528308, China.
  • 6 Guanghua School of Stomatology, Hospital of Stomatology, Guangdong Province Key Laboratory of Stomatology, Sun Yat-sen University, Guangzhou, 510095, China.
  • 7 Medical Research Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, 510120, China.
  • 8 School of Mathematics and Big Data, Foshan University, Southern Medical University, Foshan 528000, Guangzhou, 510000, China.
  • 9 Department of Endodontics, Stomatological Hospital, Southern Medical University, Guangzhou, 510000, China.
PMID: 41309490 DOI: 10.1002/advs.202509340
Abstract

Mast cells play complex and context-dependent roles within the tumor microenvironment, yet their molecular characteristics and functional diversity across human cancers remain poorly defined. In this study, single-cell RNA Sequencing and spatial transcriptomics data are integrated to comprehensively map the transcriptional and spatial heterogeneity of mast cells across ten Cancer types. A distinct proinflammatory mast cell (PMC) population is identified, characterized by strong antigen-presenting features and immune-activating potential. Mechanistic analyses show that retinoic acid (RA) signaling drives the polarization of PMCs through activation of RARα, which promotes CIITA-mediated MHC-II expression, CXCL16 secretion, and T cell recruitment and activation. Across multiple Cancer types, tumors with higher PMC abundance are associated with more favorable clinical outcomes. These findings reveal the pivotal role of RA-RARα-CIITA signaling in mast cell reprogramming and suggest that pharmacologic induction of proinflammatory mast cells may represent a promising approach to enhance antitumor immunity.

Keywords

Mast cells; cancer immunotherapy; pan‐cancer; retinoic acid; single‐cell RNA sequencing.

Figures
Products